Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-08-19
1998-02-10
Guzo, David
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 245, 544242, 544264, 568 8, 568 11, 568 36, C07H 2100, C07D23900
Patent
active
057170835
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is directed to oligomeric compounds comprising monomeric units having a backbone segment covalently bound to a phosphoramidate or phosphorothioamidate moiety. Functional groups are attached independently either at the backbone segment, at the phosphoramidate or phosphorothioamidate moieties or both. Substitutions can be effected through an optional tether group. The oligomers are synthesized having either a random or a predefined sequences of units. Randomization can be effected independently at the backbone segment, or at the phosphoramidate or phosphorothioamidate moieties, via the covalent bonding of diverse functional groups. The functional group or groups on the monomeric units can, inter alia, provide for binding of the oligomeric structures to proteins, nucleic acids, lipids and to other biological targets. In preferred embodiments, the compounds of the invention act as inhibitors of enzymes such as phospholipase A.sub.2 : as inhibitors of pathogens such as virus, mycobacterium, bacteria (gram negative and gram positive), protozoa and parasites; as inhibitors of ligand-receptor interactions such as PDGF (platelet derived growth factor), LTB4 (leukotriene B4), IL-6 and complement C5.sub.A ; as inhibitors of protein/protein interactions including transcription factors such as p50 (NF.sub.kappa B protein) and fos/jun; and for the inhibition of cell-based interactions including ICAM induction (using inducers such as IL1-.beta., TNF and LPS). In other preferred embodiments, the compounds of the invention are used as diagnostic reagents, including diagnostic reagents in the tests for each of the above noted systems, and as reagents in assays and as probes.
BACKGROUND OF THE INVENTION
Traditional processes of drug discovery involve the screening of complex fermentation broths and plant extracts for a desired biological activity or the chemical synthesis of many new compounds for evaluation as potential drugs. The advantage of screening mixtures from biological sources is that a large number of compounds are screened simultaneously, in some cases leading to the discovery of novel and complex natural products with activity that could not have been predicted otherwise. The disadvantages are that many different samples must be screened and numerous purifications must be carried out to identify the active component, often present only in trace amounts. On the other hand, laboratory syntheses give unambiguous products, but the preparation of each new structure requires significant amounts of resources. Generally, the de novo design of active compounds based on the high resolution structures of enzymes has not been successful.
In order to maximize the advantages of each classical approach, new strategies for combinatorial unrandomization have been developed independently by several groups. Selection techniques have been used with libraries of peptides (see Geysen, H. M., Rodda, S. J., Mason, T. J., Tribbick, G. & Schoofs, P. G., J. Immun. Meth. 1987, 102, 259-274; Houghten, R. A., Pinilla, C., Blondelle, S. E., Appel, J. R., Dooley, C. T. & Cuervo, J. H., Nature, 1991, 354, 84-86; Owens, R. A., Gesellchen, P. D., Houchins, B. J. & DiMarchi, R. D., Biochem. Biophys. Res. Commun., 1991, 181, 402-408), nucleic acids (see Wyatt, J. R., et al., Proc. Natl. Acad. Sci. U.S.A., (in press); Ecker, D. J., Vickers, T. A., Hanecak, R., Driver, V. & Anderson, K., Nucleic Acids Res., 1993, 21, 1853-1856) and nonpeptides (see Simon, R. J., et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 9367-9371; Zuckermann, R. N., et al., J. Amer. Chem. Soc., 1992, 114, 10646-10647; Bartlett, Santi, Simon, PCT WO91/19735; and Ohlmeyer, M. H., et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90, 10922-10926). The techniques involve iterative synthesis and screening of increasingly simplified subsets of oligomers. Monomers or sub-monomers that have been utilized include amino acids and nucleotides both of which are bi-functional. Utilizing these techniques, libraries have been assayed for activity in eithe
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Acevedo Oscar
Cook Phillip Dan
Hebert Normand
Guzo David
ISIS Pharmaceuticals Inc.
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